Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness

Natalie S Joe; Inês Godet; Nubaira Milki; Noor U I Ain; Harsh H Oza; Gregory J Riggins; Daniele M Gilkes

doi:10.1186/s13058-022-01591-3

Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness

Breast Cancer Res. 2022 Dec 28;24(1):98. doi: 10.1186/s13058-022-01591-3.

Authors

Natalie S Joe^{1

2}, Inês Godet^{1

3

4}, Nubaira Milki³, Noor U I Ain⁵, Harsh H Oza¹, Gregory J Riggins^{1

2

6}, Daniele M Gilkes^{7

8

9

10}

Affiliations

¹ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
² Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA.
⁴ Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA.
⁵ NIH NIDDK Short-Term Research Experience Program to Unlock Potential (STEP-UP), The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
⁶ Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
⁷ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. dgilkes1@jhu.edu.
⁸ Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. dgilkes1@jhu.edu.
⁹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA. dgilkes1@jhu.edu.
¹⁰ Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA. dgilkes1@jhu.edu.

Abstract

Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC₅₀) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin β4 (ITGβ4) expression and cancer stem cell properties. ITGβ4 has previously been implicated in promoting "cancer stemness," which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.

Keywords: Cancer prevention; Mebendazole; Metastasis; Triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Female
Humans
Integrin beta4
Mebendazole* / pharmacology
Mebendazole* / therapeutic use
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics

Substances

Mebendazole
Integrin beta4